A genetic variant BDNF polymorphism alters extinction learning in both mouse and human

Area of Science:

• Neuroscience
• Behavioral Genetics
• Psychiatry

Background:

• Mouse models are crucial for understanding gene function in behavior.
• The relevance of mouse models to human behavior, especially concerning genetic influences on anxiety, requires further investigation.
• The brain-derived neurotrophic factor (BDNF) gene is implicated in anxiety-related behaviors.

Purpose of the Study:

• To investigate the functional relevance of a specific single-nucleotide polymorphism (SNP) in the BDNF gene across species.
• To determine if a mouse model carrying a variant BDNF allele can recapitulate human behavioral and neural phenotypes associated with anxiety.
• To explore the potential role of this BDNF variant in anxiety disorders and the effectiveness of extinction-based therapies.

Main Methods:

• Identification of a common single-nucleotide polymorphism (SNP) in the human BDNF gene associated with anxiety-related behavior.
• Creation of an inbred genetic knock-in mouse strain expressing the variant BDNF allele.
• Phenotypic assessment of fear conditioning and fear extinction in both humans and the engineered mouse model.
• Neuroimaging (functional) to examine frontoamygdala activity in humans exhibiting the polymorphism.

Main Results:

• A specific BDNF variant was identified, showing parallel phenotypic effects in mice and humans.
• The knock-in mouse model successfully replicated the phenotypic effects observed in humans with the BDNF polymorphism.
• Both humans and mice with the variant BDNF allele demonstrated impaired extinction of conditioned fear responses.
• Atypical frontoamygdala activity was observed in humans carrying the variant BDNF allele.

Conclusions:

• The identified variant BDNF allele plays a significant role in fear extinction learning, impacting the ability to discern safety cues.
• This BDNF variant may contribute to the pathophysiology of anxiety disorders characterized by difficulties in safety learning.
• The findings suggest that treatments relying on extinction mechanisms, such as exposure therapy, might have variable efficacy depending on an individual's BDNF genotype.